Chronic pain syndromes affect 25-35% of populations around the world. The presence of chronic pain generates a massive toll on quality of life, workforce productivity and healthcare resource utilization. Although non-opiate medications have been introduced to treat chronic pain syndromes, many types of chronic/neuropathic pain do not respond to such medications (e.g., cancer-related pain, visceral pain syndromes). Drugs acting at opioid receptors and particularly ? (mu) opioid receptors (e.g., morphine, dilaudid) remain the mainstay of chronic pain therapy. However, these ? opioid receptor targeted drugs carry with them a very substantial burden of side effects, including risk of death by respiratory depression and life- long physical dependence on these compounds. More recent research has discovered that activation of other types of opioid receptors ? (delta) and ? (kappa)] can produce relief from pain. Additionally, it has been discovered that opioid receptors can form multiunit complexes at the cell surface, and activation of one receptor can promote activation of another in such complexes (positive allosteric interaction). Taking advantage of this new knowledge, a rationally designed molecule has been synthesized in Lohocla Research Corporation laboratories that can activate ? and ? opiod receptors and not affect ? receptors. This compound alleviates pain. This application is focused on further improvement of this initial (parent) molecule through molecular modeling-driven medicinal chemistry. Four new molecules which, by design, should have higher affinity and efficacy as agonists at ? and ? receptors, will be synthesized. These compounds will be tested in receptor binding assays and whole cell functional assays to generate a specificity profile and determine biological action and potency. Selected compounds will be used for bioavailability studies, and initial proof of concept studies for reversing pain in animal models of inflammatory pain syndromes. These Phase I SBIR studies should set the stage for further development through the SBIR Phase II program and completion of pre-clinical work for a most promising pain medication.